Cobalt chloride, a hypoxia-mimicking agent, targets sterol synthesis in the pathogenic fungus Cryptococcus neoformans
Cobalt chloride, a hypoxia-mimicking agent, targets sterol synthesis in the pathogenic fungus Cryptococcus neoformans
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DOI：
10.1111/j.1365-2958.2007.05844.x
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发表时间：
2007-08-01
影响因子：
3.6
通讯作者：
Chang, Yun C.
中科院分区：
文献类型：
--
作者：
Lee, Hyeseung;Bien, Clara M.;Chang, Yun C.
我们研究了模拟低氧的氯化钴在病原性真菌新生隐球菌中的作用，并证明氯化钴导致麦角甾醇生物合成中几个酶促步骤的缺陷。甾醇缺陷在缺乏Sre 1 p介导的氧敏感途径的细胞中被放大。因此，Sre 1 p和它的结合伙伴Scp 1 p是必不可少的生长在氯化钴的存在。有趣的是，参与麦角固醇生物合成的单个基因ERG 25的高拷贝挽救了这种生长缺陷。我们表明，氯化钴对scp 1三角洲和sre 1三角洲细胞的抑制作用可能导致无论是积累的非可行的甲基化甾醇或麦角甾醇的量减少。在子囊酵母，裂殖酵母，也观察到类似的结果，表明氯化钴对Sre 1 p介导的反应的影响是保守的真菌。此外，基因表达分析显示有限的重叠Sre 1 p依赖性基因激活CoCl 2和低氧的存在下。大多数基因同样受到氯化钴和低氧的影响，参与麦角甾醇的合成和铁/铜的运输。本文确定了Sre 1 p途径作为一种常见的机制，酵母细胞的感觉和适应的变化，在两个氯化钴浓度和氧气水平。
We investigated the effects of the hypoxia-mimetic CoCl2 in the pathogenic fungus Cryptococcus neoformans and demonstrated that CoCl2 leads to defects in several enzymatic steps in ergosterol biosynthesis. Sterol defects were amplified in cells lacking components of the Sre1p-mediated oxygen-sensing pathway. Consequently, Sre1p and its binding partner Scp1p were essential for growth in the presence of CoCl2. Interestingly, high copies of a single gene involved in ergosterol biosynthesis, ERG25, rescued this growth defect. We show that the inhibitory effect of CoCl2 on scp1 Delta and sre1 Delta cells likely resulted from either an accumulation of non-viable methylated sterols or a decrease in the amount of ergosterol. Similar findings were also observed in the ascomycetous yeast, Schizosaccharomyces pombe, suggesting that the effects of CoCl2 on the Sre1p-mediated response are conserved in fungi. In addition, gene expression analysis revealed limited overlap between Sre1p-dependant gene activation in the presence of CoCl2 and low oxygen. The majority of genes similarly affected by both CoCl2 and low oxygen were involved in ergosterol synthesis and in iron/copper transport. This article identifies the Sre1p pathway as a common mechanism by which yeast cells sense and adapt to changes in both CoCl2 concentrations and oxygen levels.